1. Field of the Invention
The present invention relates to endophytic Streptomycetes from higher plants having desirable biological activities. The present invention also relates to extracts and compounds obtainable from such strains demonstrating the desirable biological activities, including the munumbicin and kakadumycin compounds, and related families of biologically active compounds, are also provided. The present invention further relates to compositions comprising the extracts and compounds as well as methods of using the compositions.
2. Description of the Related Art
The bacterial order Actinomycetales includes several genera of bacteria similar to fungi in that they have a branching, filamentous structure. The branching filaments of the Actinomycetes eventually develop a network of strands called mycelium, which are similar in appearance to the mycelium of some fungi. Actinomycetes also form spores.
Actinomycetes are particularly valued for the property of producing antibiotics, with the most productive genus in this group being Streptomyces. Over 50 commercially important antibiotics have been isolated from Streptomyces spp., including streptomycin, neomycin, chloramphenicol and tetracyclines. Streptomycetes are found worldwide, and are a particularly significant as members of the soil microflora. Streptomycetes are also metabolically diverse, however, and are found in a great variety of ecological environments.
Actinomycetes, in general, are not reported to be endophytes on higher plants, though recently a Streptomyces sp. was reported on an annual plant—Lolium perenne (Guerny and Mantle, 1993). This lolium endophyte produces a weak antibiotic designated as methylalbonoursin, which is a diketopiperazine, condensed from leucine and phenylalanine. Streptomycetes which are used as a source of biologically active compounds, such as antibiotics, have all been isolated from soil.
The development of drug resistance in human pathogenic bacteria, such as Staphylococcus, Mycobacterium, Streptococcus, Enterococcus and others, places an ever increasing importance on the search for new antibiotics, as diseases caused by such bacteria represent a clear and growing threat to world health (NIH, 2001). For instance, tuberculosis is the second leading cause of death in the world, killing approximately 2.5 million people per year. Up to 30% of the world's peoples are carriers of this pathogen (NIH, 2001). The incidence of tuberculosis is rising in the world's population, in part due to the increased incidence of patients with HIV/AIDS, but also due to the development of drug resistance in strains of M. tuberculosis (Raviglione et al, 1995; Pablosmendez et al., 1997).
In addition to the problems of drug resistance in pathogenic bacteria there is also a need for more and better antimycotics, as the human population is developing more fungal infections. This is particularly an issue with HIV/AIDS patients, but also a concern with patients with organ-transplants, who must take immunosuppressive drugs to maintain continuity of the transplanted organ. In both cases, patients with these difficulties have immune systems that are weakened. Antifungal agents that are currently available, such as amphotericin B, are toxic, and often ineffective (Walsh, 1992; Walsh and Finberg, 1999; Tiphine et al., 1999).
The increased incidence of parasitic protozoan infections is a further cause of concern. The most important of these is malaria caused by Plasmodium spp. that kills up to 1.5-3 million people and produces up to nearly 500 million cases per year (NIH, 2001). It is estimated that nearly 40% of the world's population is at risk of becoming infected with malaria. Global warming as well as “airport malaria” are factors contributing to the increasing spread of this disease. Another factor contributing to the increased threat of death caused by malaria is the development of drug resistance in the Plasmodium spp. populations (NIH, 2001). In some cases, treatment of malaria and other infectious diseases has been possible with the availability of antibiotics originally derived from soil-born Streptomyces spp. (Waksman, 1967; Waksman and Lechevalier 1953; and Arai, 1976).
There is also a need for environmentally sound ways to grow the world's food, and new methods of controlling pests and pathogens are continuously needed in this field, as well (Overton et al., 1996). In the past, the major source of pesticidal agents came from organic synthesis. Recently, interest has increased for using more environmentally friendly methods in agricultural production, including naturally-occurring biological compounds.
It is an object of the present invention to provide endophytic streptomycetes from higher plants, and extracts and compounds thereof, with biological activity.